Heparin-induced thrombocytopenia

Morning Report is an occasional feature in ACP Hospitalist that analyzes the clinical and administrative aspects of a fictional but realistic
hospital case from admission to discharge. Authors of this feature discuss the patient's
clinical course and will also provide a brief overview of background, diagnosis, and
management, emphasizing whether the case was optimally managed and whether the patient
was appropriately discharged with efforts to prevent readmission.

The patient

Chief problem: Development of thrombocytopenia on day 6 of hospitalization.

History: A 46-year-old woman with a history of chronic obstructive pulmonary disease (COPD)
was admitted to the ICU with the diagnosis of acute-on-chronic, hypoxemic, hypercapnic
respiratory failure and health care-associated pneumonia. Initial interventions included
mechanical ventilation for four days and intravenous antibiotics. Heparin, 5000 U/8
h, was given for deep venous thrombosis (DVT) prophylaxis. Complete blood counts were
obtained every three days. Admission platelet count was 224 × 109 cells/L, but by day 3 it had dropped to 175 × 109 cells/L, and on day 6, platelet count was noted to be 96 × 109 cells/L.

The patient's medical history was significant for hypertension, chronic hypoxemic
respiratory failure, and COPD. She had a 50-pack-year smoking history but reported
no use of alcohol or illicit drugs. She had no known drug allergies. Hospital medications
included the following: vancomycin, 1500 mg/12 h; levofloxacin, 750 mg/d; cefepime,
2 g/12 h; pantoprazole, 40 mg/d; enalapril, 10 mg/d; ipratropium/albuterol, 0.5 mg/2.5
mg/3 mL nebule every 4 hours; and heparin, 5000 U/8 h.

Clinical course

Once progressive thrombocytopenia was identified, multiple laboratory studies were
ordered. Peripheral smear revealed thrombocytopenia with no schistocytes. Partial
thromboplastin time, prothrombin time, international normalized ratio (INR), lactate
dehydrogenase level, haptoglobin level, and complete metabolic panel were within normal
limits. A presumptive diagnosis of heparin-induced thrombocytopenia (HIT) was made
based on a “4 T's” score of 5 (see Table). Blood was sent to a reference laboratory for anti-PF4/heparin ELISA. Heparin was
discontinued, and the patient was placed on sequential compression devices for ongoing
DVT prophylaxis.

Two days later, the platelet count had dropped to 43 × 109 cells/L, and the anti-PF4/heparin ELISA result was positive, with an optical density
(OD) of 2.926. The patient was started on argatroban, and a serotonin release assay
was sent to a reference lab for confirmatory testing. Ultimately, the serotonin release
assay result was positive, and the patient was maintained on argatroban for one week
until her platelet count increased to 104 × 109 cells/L, at which time she was placed on oral apixaban, 5 mg twice daily, and was
discharged to complete an additional three weeks of therapy.

Four days later, the patient returned to the hospital with acute-on-chronic hypoxemic
respiratory failure. A CT angiogram of the chest revealed bilateral pulmonary emboli.

Case review

Q: Was our patient diagnosed correctly?

A: Yes. The 4 T's score indicated that the patient had an intermediate probability of
HIT. An anti-PF4/heparin ELISA was obtained and returned as strongly positive. Subsequently,
a functional assay (serotonin release assay) was obtained to confirm the diagnosis
and was positive.

Q: Was our patient managed and discharged appropriately?

A: No. While the 4 T's score was used appropriately to determine the probability of HIT,
the patient was managed suboptimally for the following reasons:

The patient should have been started on argatroban as soon as it was determined that
clinical probability for HIT was intermediate or higher (4 T's score ≥4) (1, 2).

Argatroban should have been continued until the platelet count was 150 × 109 cells/L or higher (1, 3).

The patient should have been transitioned from argatroban to warfarin prior to discharge,
with a minimum of five days' overlap of the two drugs (1, 2, 3). Currently, none of the direct-acting oral anticoagulants (DOACs) available in the
United States (edoxaban, dabigatran, apixaban, and rivaroxaban) are FDA-approved for
the treatment of HIT.

Bilateral lower-extremity compression ultrasonography could have been performed to
rule out occult DVT, since the presence of a DVT would influence treatment duration
of warfarin at discharge and change the diagnosis to heparin-induced thrombocytopenia
and thrombosis (HITT) (1).

Overview

Heparin-induced thrombocytopenia has a prevalence of 0.1% to 5% in patients receiving
heparin (4, 5). It is an adverse drug reaction that occurs when heparin-dependent IgG antibodies
bind to heparin/platelet factor 4 complexes to activate platelets. The result is a
hypercoagulable state that leads to thrombocytopenia (HIT) or thrombocytopenia and
thrombosis (HITT) (4).

HIT usually develops after more than five days of heparin therapy (5), with a range of four to 15 days (4, 6) in patients without heparin exposure in the preceding 100 days. Approximately 60%
of patients with HIT experience a decline in platelets five to 10 days after exposure
(5). The risk of HIT is 10 times higher with unfractionated heparin (UFH) than with
low-molecular-weight heparin (LMWH) (3, 5, 6). HIT is 1.5 to 2 times more likely to occur in women than in men (4) and is more likely in surgical or trauma patients (1% to 5%) than in medical or
intensive care patients (<1%) (5).

A diagnosis of HIT should be considered when a patient develops new thrombocytopenia
(platelet count <150 × 109 cells/L) or experiences a proportional decline in platelets of more than 30% to 50%
after heparin exposure. The most common complication of HIT is venous thrombosis such
as DVT or pulmonary embolism, but arterial thrombotic events such as myocardial infarction,
thrombotic stroke, and limb ischemia are all possible (3).

Clinical scoring systems to predict the likelihood of HIT include the HIT Expert Probability
(HEP) score and the 4T's scoring system (5). Both the 4 T's score and the HEP score consider the magnitude and timing of the
decrease in platelet count, the presence of thrombosis, and other potential causes
for the observed thrombocytopenia (4), but differ in how specific clinical features are scored.

The HEP score includes eight clinical features and has a sensitivity of 100% and a
specificity of 60% (5, 6, 7). Limitations of this scoring system include its complexity and the need for validation
in larger prospective studies (5). The 4T's scoring system, as the name implies, includes four clinical categories.
In a meta-analysis, the negative predictive value of a low 4 T's score was 99.8%,
while the positive predictive value of an intermediate or a high 4 T's score was 14%
or 64%, respectively (8).

Laboratory work-up and management of the patient with suspected HIT hinge on the clinical
probability of the diagnosis. For a patient with a low clinical probability (4 T's
score of ≤3), no further laboratory work-up is necessary and heparin therapy can
be continued. For a patient with an intermediate to high clinical probability of HIT
(4 T's score ≥4), heparin should be discontinued, an alternate anticoagulant should
be initiated, and an anti-PF4/heparin ELISA should be obtained (1). The anti-PF4/heparin ELISA has a sensitivity of 99% (5), so if the anti-PF4/heparin ELISA result is negative, HIT is unlikely and heparin
may be reintroduced.

If the anti-PF4/heparin ELISA is weakly positive (OD of 0.4 to 0.99) and the patient
has an intermediate clinical probability (4 T's score of 4 to 5), HIT is also unlikely
and heparin may be reinitiated. However, if the anti-PF4/heparin ELISA is weakly positive
(OD of 0.4 to 0.99) and the patient has a high clinical probability (4 T's score 6
to 8), a functional assay (serotonin release assay or heparin-induced platelet activation
assay) should be obtained. Last, in patients with intermediate or high clinical probability
(4 T's score ≥4), if the anti-PF4/heparin ELISA is moderately or strongly positive
(OD ≥1.00), a functional assay should be obtained. These functional assays offer
both high sensitivity (90% to 98%) and specificity (90% to 95%). If these assays are
positive, HIT is likely, and if they are negative, HIT is unlikely (1).

Treatment of HIT begins with stopping all heparin products and starting an alternate
anticoagulant. The American College of Chest Physicians' 2012 guidelines “Treatment
and Prevention of Heparin-Induced Thrombocytopenia” recommend anticoagulation
with lepirudin, argatroban, or danaparoid (3). Of these agents, both lepirudin and danaparoid have been discontinued in the United
States, thus the direct thrombin inhibitor argatroban is the only FDA-approved agent
currently available to treat HIT. Alternative anticoagulation should be maintained
until the platelet count increases to at least 150 × 109 cells/L, at which time a vitamin K antagonist (VKA) can be initiated at dosages of
5 mg or less (1, 3). It is recommended that VKA and alternate anticoagulant therapy overlap for a minimum
of five days and until the INR is within the target range consistently before the
patient is transitioned to VKA monotherapy (1, 2, 3). Patients with HIT should receive therapeutic anticoagulation for four weeks (2, 3). Bilateral lower-extremity ultrasound to rule out occult DVT may be considered (1), since the presence of a thrombus would change the diagnosis from HIT to HITT and
change the treatment duration to three months (1, 2).

Interventions that are not currently recommended for the treatment of HIT include
fondaparinux, DOACs, and prophylactic platelet transfusion. The 2012 guidelines did
not recommend fondaparinux because the highest level of evidence at that time was
limited to case series (3). Although none of the DOACs are approved for HIT, there are some published reports
of their use (9, 10, 11, 12). Likewise, prophylactic platelet transfusions are not routinely recommended, but
platelet transfusion may be employed in the event of bleeding or during a procedure
with a high risk of bleeding (2, 3).

Summary

Several potential errors are highlighted in this case, including delay and early discontinuation
of argatroban therapy. As a result of this suboptimal management, the patient developed
a thrombotic complication, highlighting the importance of accurate recognition and
treatment of heparin-induced thrombocytopenia.

Dr. Thomas is an associate professor of internal medicine at the West Virginia School
of Osteopathic Medicine in Lewisburg, W. Va.

ACP Hospitalist provides news and information for hospitalists, covering the major issues in the field. All published material, which is covered by copyright, represents the views of the contributor and does not reflect the opinion of the American College of Physicians or any other institution unless clearly stated.